Minimal improvement in the 12-15 month survival of patients with glioblastoma mutliforme (GBM) has been achieved despite in depth knowledge of pathogenic lesions and decades of advances in neurosurgery, radiation therapy and clinical trials. A central issue that confounds successful treatment is the heterogeneous nature of this aggressive tumor. This heterogeneity presents phenotypically as mixed cytological subtypes, genotypically as mutations and gene amplifications, and transcriptionally as regional differences in gene expression. As a result, multiple and spatially distinct heterotypic populations exist within a GBM, making any lesion- or pathway-specific therapy less effective. While much effort has been placed on understanding the interactions between heterotypic tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within these neoplasms. In GBM, amplification of the epidermal growth factor receptor, a hallmark mutation present in 50% of cases, is often detected in a heterogeneous manner and frequently associated with structural alterations. The most common of these alterations, ?EGFR, (also known as de2-7EGFR, deltaEGFR and EGFR*) results in a constitutively active mutant receptor with tumor enhancing capability. This ability is lacking from amplified wtEGFR despite its highly pervasive tumor expression in comparison to focally occurring ?EGFR. By modeling this type of genetic heterogeneity in vivo, we have determined that an IL-6 paracrine mechanism driven by ?EGFR can recruit wtEGFR-expressing cells into accelerated proliferation and therefore result in the maintenance of heterogeneity. Given the ineffectiveness of EGFR-directed therapeutics, we postulate that ?EGFR/wtEGFR sub-population interactions not only enhance aggressive tumor growth but also play a role in therapeutic resistance. The overall goal of this project is to dissect the mechanisms whereby GBM receptor heterogeneity drives tumor aggressiveness and therapeutic resistance. The following lines of experimentation will be carried out: 1) genetic and biochemical analysis as well as tumor heterogeneity modeling in mice will determine critical effectors intrinsic to ?EGFR- and wtEGFR- signaling that mediate heterogeneity maintenance; 2) mass spectrometry, genetic and biochemical analysis will determine the mechanism of IL-6 receptor-mediated cross- talk activation of wtEGFR; and 3) genetic and pharmacological inhibition of identified effectors will be used to uncouple heterotypic glioma cell interactions to enhance therapeutic efficacy.